The therapeutic effect of tyrosine kinase inhibitor in 5/6 nephrectomized rats

酪氨酸激酶抑制剂对5/6肾切除大鼠的治疗作用

基本信息

批准号：
22790805
负责人：
IYODA Masayuki
金额：
$ 2.25万
依托单位：
Showa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22790805/
关键词：
チロシンキナーゼ阻害薬慢性腎臓病腎線維化慢性腎不全

项目摘要

Nilotinib is a second-generation tyrosine kinase inhibitor that demonstrates a 30-fold increase in activity against Bcr-Abl, and a similar level of activity against the PDGF receptor(PDGFR) and c-Kit when compared to imatinib, a compound that has been previously shown to exhibit therapeutic benefits in animal models of renal disease, including cryoglobulinemic membranoproliferative glomerulonephritis and nephrotoxic serum nephritis. In the current study, we investigated the role of nilotinib in the progression of established renal failure. Adult male Sprague Dawley rats were subjected to 5/6 nephrectomy or laparotomy(sham-operated). Rats with 5/6 nephrectomy were then administered either nilotinib(45mg/kg) or vehicle via daily oral gavage from 2 weeks after surgery, and for a period of 8 weeks. Blood pressure(BP), proteinuria(U-P), serum creatinine(Cr) and body weight(BW) were measured periodically. Renal morphological investigations were performed at sacrifice. In vitro, we used renal … More fibroblasts(NRK49F) and primary mesangial cells. Cells were pretreated with nilotinib or medium alone, and collagen type I synthesis and PDGFR. phosphorylation induced by angiotensin II or PDGF-BB were analyzed by real-time RT-PCR and immunoblotting. BP and BW were comparable between the two treatment groups throughout the study. Following 6 and 8 weeks of treatment, serum Cr levels in the nilotinib-treated rats were significantly lower than that of the vehicle-treated rats. When compared to vehicle treatment, nilotinib-treated rats demonstrated reduced U-P at 1 week after treatment. This reduction was maintained over the course of the study. Nilotinib treatment also resulted in a decrease in remnant kidney hypertrophy, in addition to reduced scores of glomerulosclerosis and tubulointerstitial damage. Renal cortical mRNA for collagen type I, TGF-β, fibronectin, and PAI-1 were also significantly decreased in the nilotinib treated group. In vitro, nilotinib blocked collagen type I/GAPDH mRNA production induced by angiotensin-II in renal fibroblasts and mesangial cells. Nilotinib also decreased collagen type I/GAPDH mRNA levels and prevented PDGFR. phosphorylation induced by PDGF-BB in mesangial cells. Nilotinib treatment significantly attenuates renal fibrosis in vivo and in vitro. Our results suggest that nilotinib may prove useful in limiting the progression of chronic renal disease to end-stage renal failure. Less

尼洛替尼是一种第二代酪氨酸激酶抑制剂，证明对BCR-ABL的活性增加了30倍，并且与伊马替尼相比，对PDGF受体（PDGFR）（PDGFR）和C-KIT的活性水平相似。肾小球肾炎和肾毒性血清肾炎。在当前的研究中，我们研究了尼洛替尼在既定肾衰竭进展中的作用。成年雄性Sprague Dawley大鼠进行5/6肾切除术或剖腹手术（假手术）。然后通过每日口腔饲料从手术后的2周，持续8周，通过每日口腔饲料进行尼洛替尼（45mg/kg）或车辆进行5/6肾切除术的大鼠。定期测量血压（BP），蛋白尿（U-P），血清肌酐（CR）和体重（BW）。牺牲时进行了肾脏形态研究。在体外，我们使用了肾脏…更多的成纤维细胞（NRK49F）和原代细胞。单独用尼洛替尼或单独培养基预处理细胞，以及I型合成和PDGFR。血管紧张素II或PDGF-BB诱导的磷酸化通过实时RT-PCR和免疫印迹分析。在整个研究中，两种治疗组之间的BP和BW是可比的。治疗6周和8周后，尼洛替尼治疗的大鼠的血清CR水平明显低于媒介物处理的大鼠。与媒介物治疗相比，尼洛替尼治疗的大鼠在治疗后1周表现出U-P降低。在整个研究过程中，这种减少是维持的。尼洛替尼治疗还导致残留的肾脏肥大降低，除了肾小球硬化和结核损伤的评分降低外。 Nilotinib处理组的胶原蛋白I型，TGF-β，纤连蛋白和PAI-1的肾皮质mRNA也得到了显着改善。在体外，尼洛替尼阻塞了血管紧张素II诱导的I型胶原蛋白/GAPDH mRNA的产生，在肾成纤维细胞和膜细胞中。尼洛替尼还改善了I/GAPDH mRNA型胶原蛋白水平，并防止了PDGFR。 PDGF-BB在弥赛亚细胞中诱导的磷酸化。尼洛替尼的治疗显着减弱了体内和体外的肾纤维化。我们的结果表明，尼洛替尼可能被证明可用于限制慢性肾脏疾病对终末肾衰竭的发展。较少的